Exercise and immunometabolic regulation in cancer

Abstract

Unhealthful lifestyle factors, such as obesity, disrupt organismal homeostasis and accelerate cancer pathogenesis, partly through metabolic and immunological dysregulation. Exercise is a prototypical strategy that maintains and restores homeostasis at the organismal, tissue, cellular and molecular levels and can prevent or inhibit numerous disease conditions, including cancer. Here, we review unhealthful lifestyle factors that contribute to metabolic and immunological dysregulation and drive tumourigenesis, focusing on patient physiology (host)-tissue-tumour microenvironment interactions. We also discuss how exercise may influence distant tissue microenvironments, thereby improving tissue function through both metabolic and immunospecific pathways. Finally, we consider future directions that merit consideration in basic and clinical translational exercise studies.

Figure 1:

Exercise-induced protection from tissue-specific perturbations in organs involved in cancer regulation or prone to malignancy. Blue boxes contain illustrative examples in the liver, colon and bone marrow. Grey boxes indicate examples of tissues where data to support exercise-induced regulation of tissue biology in the absence of frank malignancy is currently lacking. NAFLD: non-alcoholic fatty liver disease; AMPK: adenosine monophosphate kinase; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; TNFα: tumour necrosis factor alpha; IL: interleukin: IL; KC: keratinocyte chemoattractant; MCP-1: monocyte chemoattract protein; COX2: cyclooxygenase-2; HSPC: hematopoietic stem and progenitor cell; Cxcl12: C-X-C motif chemokine 12.

Figure 2:

Exercise-induced regulation of immune and metabolic function in the TME. (A) Exercise alters the immune composition of the TME (blue boxes), decreasing the proportion of innate immune cell populations (macrophages and myeloid derived suppressor cells (MDSCs) and increasing CD3+ T cells and NK cells. Furthermore, the ratio of CD8+ T cells versus regulatory T cells (Treg), as well as the activation of CD8+ T cells (CD69+) is increased with exercise. Exercise also alters TME metabolism (green boxes). Decreased hypoxia and increased vascularization occur alongside decreased levels of lactate and MCT1, and the relative concentration of metabolites that comprise the TCA cycle are also reduced. Increased intratumoural AMPK activity and reduced AKT, mTOR, Pi3K, and p42/p44-MAPK have all been reported with exercise. T cells and NK cells are required for exercise-induced tumour inhibition in mouse models of cancer. (B) Proposed immunometabolic mechanisms that may drive exercise-induced inhibition or delay of tumourigenesis. NK: natural killer; MCT-1: Monocarboxylate transporter 1; TCA: tricarboxylic acid cycle; AMPK: adenosine monophosphate kinase; mTOR: mammalian target of rapamycin; Pi3K; Phosphoinositide 3-kinase; MAPK: mitogen-activated protein kinase.